The growth of siRNA-based therapeutics: Updated clinical studies

被引：329

作者：

Zhang, M. May ^{[1
]}

Bahal, Raman ^{[1
]}

Rasmussen, Theodore P. ^{[1
]}

Manautou, Jose E. ^{[1
]}

Zhong, Xiao-bo ^{[1
]}

机构：

[1] Univ Connecticut, Sch Pharm, Dept Pharmaceut Sci, Storrs, CT 06269 USA

来源：

BIOCHEMICAL PHARMACOLOGY | 2021年 / 189卷

关键词：

siRNAs; Drug development; FDA approval; Clinical trial; FAMILIAL AMYLOIDOTIC POLYNEUROPATHY; ISCHEMIC OPTIC NEUROPATHY; DOUBLE-STRANDED-RNA; PHARMACOKINETIC PROPERTIES; TARGETING ANTITHROMBIN; CHEMICAL-MODIFICATIONS; MESSENGER-RNA; HEMOPHILIA-A; INTERFERENCE; DELIVERY;

D O I：

10.1016/j.bcp.2021.114432

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

More than two decades after the natural gene-silencing mechanism of RNA interference was elucidated, small interfering RNA (siRNA)-based therapeutics have finally broken into the pharmaceutical market. With three agents already approved and many others in advanced stages of the drug development pipeline, siRNA drugs are on their way to becoming a standard modality of pharmacotherapy. The majority of late-stage candidates are indicated for rare or orphan diseases, whose patients have an urgent need for novel and effective therapies. Additionally, there are agents that have the potential to meet the need of a broader population. Inclisiran, for instance, is being developed for hypercholesterolemia and has shown benefit in patients who are uncontrolled even after maximal statin therapy. This review provides a brief overview of mechanisms of siRNA action, physiological barriers to its delivery and activity, and the most common chemical modifications and delivery platforms used to overcome these barriers. Furthermore, this review presents comprehensive profiles of the three approved siRNA drugs (patisiran, givosiran, and lumasiran) and the seven other siRNA candidates in Phase 3 clinical trials (vutrisiran, nedosiran, inclisiran, fitusiran, teprasiran, cosdosiran, and tivanisiran), summarizing their modifications and delivery strategies, disease-specific mechanisms of action, updated clinical trial status, and future outlooks.

引用

页数：12

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